ORGANIC LETTERS
Pd-Catalyzed r-Arylation of Nitriles and Esters and γ-Arylation of Unsaturated Nitriles with TMPZnCl 3 LiCl
2011 Vol. 13, No. 7 1690–1693
Stephanie Duez,† Sebastian Bernhardt,† Johannes Heppekausen,† Fraser F. Fleming,*,‡ and Paul Knochel*,† Department Chemie, Ludwig-Maximilians-Universit€ at, Butenandtstrasse 5-13, 81377, M€ unchen, Germany, and Department of Chemistry and Biochemistry, Duquesne University, 600 Forbes Avenue, Mellon Hall, Pittsburgh, Pennsylvania 15282, United States
[email protected];
[email protected] Received January 21, 2011
ABSTRACT
Using TMPZnCl 3 LiCl as a kinetically highly active base, nitriles and esters undergo a Pd-catalyzed R-arylation under mild conditions. Remarkably, in the case of R,β- or β,γ-unsaturated nitriles, a regioselective γ-arylation or a γ-alkenylation is observed.
The Pd-catalyzed arylation of carbonyl derivatives and related functional groups has significantly extended the scope of enolate chemistry.1 Several bases have been used †
Ludwig-Maximilians-Universit€at. Duquesne University. (1) (a) Johansson, C.; Colacot, T. Angew. Chem., Int. Ed. 2010, 49, 676. (b) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953. (c) Bellina, F.; Rossi, R. Chem. Rev. 2009, 110, 1082. (2) Mulvey, R.; Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46, 3802. (3) For examples with ketone, malonate, and amide enolates, see: (a) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489. (b) Colacot, T. J. Org. Lett. 2004, 6, 3731. (c) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444. (d) Ackermann, L.; Spatz, J. H.; Gschrei, C. J.; Born, R.; Althammer, A. Angew. Chem., Int. Ed. 2006, 45, 7627. (e) Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1998, 36, 1664. (f) Cristau, H. J.; Vogel, R.; Taillefer, M.; Gradas, A. Tetrahedron Lett. 2000, 41, 8457. (g) De Filippis, A.; Pardo, D. G.; Cossy, J. Tetrahedron 2004, 60, 9757. (h) Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew. Chem., Int. Ed. 2006, 45, 5852. (i) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976. (4) For examples with ester enolates, see: (a) Bentz, E.; Moloney, M. G.; Westaway, S. M. Tetrahedron Lett. 2004, 45, 7395. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (c) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1549. (d) Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545. (e) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 11176. (f) Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557. (g) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996. (h) Biscoe, M. R.; Buchwald, S. L. Org. Lett. 2009, 11, 1773. (i) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5182.
to generate R-metalated nitriles and carbonyl derivatives. These metal enolates produce, after reductive elimination of an intermediate arylpalladium(II), various R-arylated carbonyl compounds.2-5 Hagadorn has reported the use of TMP2Zn to deprotonate amides and esters. He
‡
10.1021/ol200194y r 2011 American Chemical Society Published on Web 03/02/2011
(5) For examples with metalated nitriles, see: (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330. (b) You, J.; Verkade, J. G. J. Org. Chem. 2003, 68, 8003. (c) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824. (d) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051. (6) (a) Hlavinka, M. L.; Hagadorn, J. R. Tetrahedron Lett. 2006, 47, 5049. (b) Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26, 4105. (7) Huang, D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2010, 49, 5757. (8) Renaudat, A.; Jean-Gerard, L.; Jazzar, R.; Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261. (9) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 2958. (b) Wunderlich, S.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7685. (c) Wunderlich, S.; Knochel, P. Org. Lett. 2008, 10, 4705. (d) Wunderlich, S.; Knochel, P. Chem. Commun. 2008, 6387. (e) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (f) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun. 2009, 5615. (g) Rohbogner, C. J.; Wirth, S.; Knochel, P. Org. Lett. 2010, 12, 1984. (h) Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J. Org. Chem. 2010, 75, 4686. (i) Wunderlich, S.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 1501. (j) Wunderlich, S.; Kienle, M.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 7256. (k) Wunderlich, S.; Knochel, P. Chem.; Eur. J. 2010, 16, 3304. (l) Wunderlich, S.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 9717. (m) Jeganmohan, M.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 8520.
performed Pd-catalyzed cross-couplings using Pd2dba3 and tBu3P as catalytic system.6 The choice of the appropriate base, the palladium catalyst, and the reaction conditions is essential for obtaining high yields. Recently, Hartwig reported silyl ketene acetals as enolate equivalents in a new Pd-catalyzed γ-arylation of R,β-unsaturated esters.7 In an alternative approach, Baudoin developed a direct β-arylation of carbonyl compounds through an Rmetalation-elimination-addition sequence.8 We developed a range of LiCl-solubilized TMP-bases9 (TMP = 2,2,6,6-tetramethylpiperidyl) which directly generate functionalized organometallics ideally suited for transition metal coupling. The bases are monomeric in solution, bear a sterically hindered TMP-moiety coordinated to LiCl, and display an exceptionally high kinetic basicity. Contrary to less hindered amines such as iPr2NH or (Me3Si)2NH, TMPH does not slow down Pd-catalyzed Negishi cross-couplings.10 These bases are excellent for deprotonating various functionalized aromatics and heteroaromatics. We envisioned using some of these TMPbases to generate metal enolates directly to improve subsequent transition metal couplings. Herein, we report the use of TMPZnCl 3 LiCl8e-h (1) for the Pd-catalyzed Rarylation of nitriles and esters as well as a new γ-arylation and γ-alkenylation of unsaturated nitriles. Exploratory optimizations revealed a delicate dependence on the nature of the base, palladium source, and ligand for sequential deprotonation-arylations. Optimally, treating a benzylic nitrile such as 2a with TMPZnCl 3 LiCl (1: 1.5 equiv, THF, 25 °C, 10 min) followed by the addition of Pd(OAc)2 (2 mol %), SPhos ligand11 (4 mol %), and ethyl 4-bromobenzoate (3a: 0.8 equiv, 50 °C, 4 h) produces the mono-R-arylated product 4a as the sole product in 83% yield (Table 1, entry 1). This procedure proved to be general and is applicable to benzylic nitriles bearing either an electron-withdrawing group (2a,b) or an electron-donating group (2c). Consequently, the reaction with various aryl bromides (3a-c) affords the arylated nitriles 4a-e in 79-89% yield (Table 1). A competitive bis-arylation of aliphatic nitriles may complicate the reaction outcome. Verkade has shown the utility of a bicyclic proazaphosphatrane for selectively performing the mono-arylation of metalated nitriles.5d Hartwig developed a more general approach using trimethylsilylalkylnitriles in the presence of ZnF2 for avoiding bis-arylation.5c Interestingly, by using TMPZnCl 3 LiCl as a base, the primary aliphatic nitrile valeronitrile (2d) undergoes a selective mono-arylation with 4-bromoaniline (3d: 0.8 equiv, THF, 50 °C, 2 h) and Pd(OAc)2 (2 mol %), SPhos (4 mol %) yielding the aniline derivative (4f) in 74% yield. Remarkably, a free NH2- group in the aryl bromide (10) Manolikakes, G.; Schade, M. A.; Hernandez, C. M.; Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765. (11) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (c) Altman, R. A.; Buchwald, S. L. Nat. Protoc. 2007, 2, 3115. (d) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. Org. Lett., Vol. 13, No. 7, 2011
Table 1. R-Arylation of Benzylic Nitriles with TMPZnCl 3 LiCl
entry
2
3
1 2 3 4 5
2a, R1 = CO2Et 2a, R1 = CO2Et 2b, R1 = CN 2c, R1 = OMe 2c, R1 = OMe
3a, R2 = CO2Et 3c, R2 = OMe 3a, R2 = CO2Et 3a, R2 = CO2Et 3b, R2 = CN
a Yield of isolated analytically pure product. TMPZnCl 3 LiCl was used.
4 yield (%)a 4a (83) 4b (89)b 4c (80) 4d (79) 4e (85) b
2.0 equiv of
Table 2. R-Arylation of Aliphatic Nitriles with TMPZnCl 3 LiCl
a
Yield of isolated analytically pure product. b The reaction time for this example was 26 h.
(3d) is well tolerated (Table 2, entry 1). This selective mono-arylation occurs with various functionalized aryl and heteroaryl bromides (3a-e) furnishing the arylated nitriles (4g-j) in 64-89% yield (Table 2, entries 2-5). As expected, the prototypical cyclic nitrile, cyclohexanecarbonitrile (2e), reacts under the same conditions (Pd(OAc)2 (2 mol %), SPhos (4 mol %)) with the aryl bromides 3b,c (0.8 equiv, 50 °C, 3 h) to afford nitriles (4k,l) efficiently in 73-92% isolated yield (Table 2, entries 6 and 7). In contrast to previous nitrile arylations,5a-d the use of TMPZnCl 3 LiCl (1) allows cross-coupling under milder conditions (50 °C) and with shorter reaction times. Also, 1691
Scheme 1. R-Arylation of Ethyl Esters
Scheme 2. γ-Arylation of Unsaturated Nitriles (7a or 9) with an Aryl Bromide (3c)
Table 3. γ-Arylation of Unsaturated Nitriles
sensitive ester and nitrile substituents are tolerated in the aryl bromides. Prior palladium-catalyzed arylations of primary esters often required the sterically protected tert-butyl esters.4d-j Under our new conditions using TMPZnCl 3 LiCl (1), arylations are readily performed with ethyl esters. Thus, the reaction of ethyl butyrate (5a: 1.0 equiv) with TMPZnCl 3 LiCl (1: 1.5 equiv, THF, 25 °C, 10 min) followed by the addition of Pd(OAc)2 (2 mol %), SPhos (4 mol %), and 4-bromoanisole 3c (0.8 equiv, 25 °C, 1 h) provides the polyfunctional arylated ester (6a) in 96% isolated yield (Scheme 1). The presence of an ethyl ester in the aryl bromide is also tolerated, providing that the reaction is performed at 50 °C with 2 equiv of ethyl butyrate (5a). With these modifications, the expected arylated ethyl ester (6b) is isolated in 80% yield.12 Similarly, the secondary ester ethyl isobutyrate (5b) undergoes the expected cross-coupling at 50 °C giving the R-arylated ethyl ester (6c) in quantitative yield (Scheme 1). γ-Arylation reactions of R,β-unsaturated carbonyl compounds have been well-studied for unsaturated ketone or aldehydes.13 Only recently have γ-arylations been examined with unsaturated esters.6 Using TMPZnCl 3 LiCl (1), we have performed the first arylations of R,β- and β,γunsaturated nitriles and observe an exceptionally regioselective γ-arylation. Thus, the reaction of cyclohexene-1carbonitrile (7a: 1.0 equiv) with TMPZnCl 3 LiCl (1: 2.0 equiv, THF, 25 °C, 10 min) followed by the addition of 4-bromoanisole (3c: 0.8 equiv) and the usual catalytic system at 50 °C for 1 h furnishes regioselectively the γarylated cyclohexene carbonitrile (8a) in 95% yield (Scheme 2). Performing the arylation reaction with the isomeric β,γ-unsaturated nitrile cyclohexene-2-carbonitrile (12) Performing the arylation reaction at 25 °C results in extensive addition reactions of the intermediate zinc enolate to the ester function of 3a. Conducting the reaction at 50 °C with 2 equiv of 5a leads to the best results. This may be explained by a higher catalyst activity at this temperature. (13) (a) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998, 39, 6203. (b) Varseev, G. N.; Maier, M. E. Org. Lett. 2005, 7, 3881. (c) Martı´ n, R.; Buchwald, S. Angew. Chem., Int. Ed. 2007, 46, 7236. (d) Hyde, A.; Buchwald, S. Angew. Chem., Int. Ed. 2008, 47, 177. (e) Hyde, A. M.; Buchwald, S. L. Org. Lett. 2009, 11, 2663. 1692
a Yield of isolated analytically pure product. b The double bond is conjugated with the aromatic ring. c 2.0 equiv of nitrile was used. d 2.5 equiv of nitrile was added over 60 min to the reaction mixture.
(9) led under the same conditions to 8a in 80% yield. This somewhat lower yield was attributed to the self-condensation reaction of 9.14 This side reaction could be avoided by adding the base TMPZnCl 3 LiCl (1) to a mixture of the nitrile 9, the aryl bromide 3c, and the Pd-catalytic system at 25 °C and stirring the reaction mixture at 50 °C for 1 h. Under these optimized conditions, the γ-arylated nitrile 8a is obtained in 94% yield (Scheme 2). The arylation of alkenenitriles is similarly effective for a range of aryl bromides bearing various functional groups (Table 3, CO2Et, Cl, F: 3f-h) giving the γ-arylated R,βunsaturated nitriles 8b-d in 69-74% yield (Table 3, (14) Cargill, R. L.; Bushey, D. F.; Good, J. J. J. Org. Chem. 1979, 44, 300. Org. Lett., Vol. 13, No. 7, 2011
Scheme 3. Stereo- and Regioselective (E) and (Z) γ-Alkenylation of the Unsaturated Nitrile 9
entries 1-3). Interestingly, in the case of 4- bromobenzonitrile (3b), the γ-arylation occurs with concomitant migration of the double bond into conjugation with the aromatic ring, furnishing the allylic nitrile 8e in 67% yield (Table 3, entry 4). Cross-coupling of cyclohexene-1-carbonitrile 7a with the unprotected 5-bromoindole (3i) leads to the functionalized indole (8f) in 60% yield (Table 3, entry 5). The open-chain 2-phenyl-substituted R,β-unsaturated nitrile (Z)-2-phenylpent-2-enenitrile (7b) reacts similarly under the same conditions. Coupling 7b with various aryl bromides (3b,c, 3j-l) provides the γ-arylated Z-unsaturated nitriles 10a-e in 55-76% yield, maintaining the olefin stereochemistry (Table 3, entries 6-10). In contrast to enolate arylations, the corresponding alkenylation is particularly rare6,15 and is unknown for nitriles. The alkenylation of unsaturated nitriles 7b and 9 was readily achieved with TMPZnCl 3 LiCl (1) with complete γ-regioselectivity. Thus, the reaction of the β,γunsaturated nitrile 9 (1.0 equiv) with either (E)- or (Z)-1iodohex-1-ene ((E)- or (Z)-11a) affords the corresponding unsaturated nitriles (E)-12a and (Z)-12a in 85-88% yield with perfect retention of the double bond stereochemistry (Scheme 3). Increasing the steric demand in the alkenyl iodide is similarly effective with the Pd-catalyzed reaction (15) (a) Negishi, E.-I.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichim. Acta 2005, 38, 71. (b) Watanabe, S.-i.; Ikeda, T.; Kataoka, T.; Tanabe, G.; Muraoka, O. Org. Lett. 2003, 5, 565.
Org. Lett., Vol. 13, No. 7, 2011
Scheme 4. Stereo- and Regioselective (E) and (Z) γ-Alkenylation of the Unsaturated Nitrile 7a
of 1-iodocyclohex-1-ene 11b and cyclohex-2-enecarbonitrile (9) giving the diene nitrile 12c in 64% yield (Scheme 3). In the case of the R,β-unsaturated nitrile (7b), the configuration of both double bonds is controlled, furnishing after the reaction with E- or Z-11a the (Z,Z) and (Z,E) skipped dienes (Z,Z)-12b and (Z,E)-12b with high diastereoselectivity (>99% (Z,Z) or (Z,E)) (Scheme 4). In summary, we have reported a practical Pd-catalyzed arylation of zincated nitriles and ester enolates with diverse, functionalized aryl bromides. Highly regioselective γ-arylation or γ-alkenylation of R,β- or β,γ-unsaturated nitriles faithfully translate the vinyl iodide and unsaturated nitrile stereochemistry into a variety of γ-substituted unsaturated nitriles. Acknowledgment. We thank the Fonds der Chemischen Industrie, the European Research Council (ERC), and the Deutsche Forschungsgemeinschaft (DFG) for financial support. Prof. F. Fleming thanks the Center of Advanced Studies, Ludwig Maximilians-Universit€at M€ unchen (CAS) for a visiting professor fellowship. We also thank BASF AG (Ludwigshafen) and Chemetall GmbH (Frankfurt) for the generous gift of chemicals. Supporting Information Available. Experimental procedures and full characterization of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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